Vinyl-substituted phthalans

ABSTRACT

Organic compounds of the class vinyl substituted phthalans are preared chemically from the corresponding vinyl isobenzofurylium compounds. The novel compounds are useful for their antidepressant activity.

United States Patent [72] Inventors FrancisJosephMcEvoy Continuation-impart of application Ser. No. 747,832, July 26, 1968, now abandoned. This application Aug. 8, 1969, Ser. No. 848,685

[54] VINYL-SUBSTITUTED PHTHALANS 8 Claims, No Drawings 52 us. Cl 260/240 0, 260/240 E, 260/247], 260/268 H, 260/294.7 D,

511 Int. Cl c070 5/32 [50] Field of Search 260/3462 R, 240 D, 240 E, 268

[56] References Cited OTHER REFERENCES Chemical Abstracts I, vol. 64, cols. 3448 to 3449 (I966) Chemical Abstracts ll, vol. 66, page 3595, abstract No. 37770(l967) Chemical Abstracts lll, vol. 66, pages 6l43 to 6144 (abstract No. 65,392 in) April 10, 1967 Primary Examiner-John D. Randolph Attorney- Ernest Y. Miller ABSTRACT: Organic compounds of the class vinyl substituted phthalans are preared chemically from the corresponding vinyl isobenzofurylium compounds. The novel compounds are useful for their antidepressant activity.

VINYLSUBSTITUTED PI II'HALAN S This application is a continuation-in-part of application Ser. No. 747,832, filed July 26, 1968, now abandoned.

SUMMARY OF THE INVENTION This invention relates to novel organic compounds and is more particularly concerned with novel vinyl substituted phthalans and method of preparation.

The novel compounds of this invention can be represented by the following formula: 7'

wherein R, and R are members of the group consisting of hydrogen and lower alkyl; R is a member of the group consist- 30 ing of hydrogen, lower alkyl, and lower all oxycarbonyl; R is lower alkyl; R;, and R, taken together with nitrogen 0 is a member of the group consisting of 4-morpholinyl,

polymethyleneimino, l-lower alkyl-4-piperazinyl, l-piperazinyl, and l-lower alkoxy carbonyl-4-piperazinyl; R is a member of the group consisting of hydrogen and lower alkyl; R and R are members of the group consisting of hydrogen, and lower alkyl; R, is a member of the group consisting of thienyl, furyl, indanyl, naphthyl, lower alkoxynaphthyl, phenyl.

cycloalkylphenyl, halophenyl, a,a,a-trifluorotolyl, lower alkylphenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyph enyl, and biphenyl; n is an integer of one to three, and nontoxic acid addition salts thereof.

The novel compounds of this invention react with lower alkyl halides to form lower alkyl quaternary ammonium halides. These salts are also within the scope of the present invention.

The novel compounds are, in general, basic. off-white or tan colored, gunirny solids. Acid addition salts of the compounds, as for eitarnple, salts of fumaric, hydrochloric, sulfuric, oxalic or perchloric acid, are crystalline solids. The novel compounds of the present invention can be prepared as shown in the following flowsheet.

wherein R,, R R R R R R R and n are as defined hereinbefore, R is lower alkyl, X is halogen and R is In accordance with the above flowsheet, treatment of a lower alkyl o-phthalate (l) with a methyl magnesium halide, followed by treatment with perchloric acid gives the oxonium perchlorate (ll). Treatment of this substrate with a substituted 'benzaldehyde, naphthaldehyde, a substituted naphthaldehyde,

indamecarboxaldehyde, thiophenecarboxaldehyde, or furancarboxaldehyde furnishes the vinyloxonium perchlorate (V). Altemately, (V) may be prepared from phthalide or a 3,3-disubstituted phthalide (11]). Thus, reaction of (Ill) with a styryl magnesium halide affords the l-styryll-hydroxyphthalan (Vl), which is transfonned by perchloric acid into the styryloxonium perchlorate (V). Treatment of this oxonium salt with the appropriate organometallic derivative furnishes the l-aminosubstituted alkyl-l-styrylphthalan (IV). This latter reaction is generally carried out in the presence of an excess of the appropriate Grignard reagent in order to insure an effective alkylation in a reasonable period of time. These alkylation reactions are usually carried out in an inert solvent such as diethyl ether, tetrahydrofuran, dioxane ethylene glycol dimethyl ether, diethylene glycol, dibutyl ether, and the like. Particularly advantageous is the use of diethylene glycol dibutyl ether. These reactions are generally conducted at temperatures of between about 30 C. and about 120 C., with the preferred temperature being from about 60 C. to 100 C. When the alkylation has been achieved, usually after heating from about 4 to about 24 hours, the desired products (IV) are generally obtained by decomposing the excess Grignard reagent, followed by purification of the crude product by methods well known to those skilled in the art. Compounds of formula (IV) serve as intermediates for the preparation of other compounds of the present invention. Thus, when the compounds of formula (IV), wherein R is methyl, are treated with a lower alkoxy carbonyl halide, the urethans (Vll) result. Saponification of (VI!) affords the compounds (Vlll). Similar treatment of compounds of formula (IV) wherein R and R taken together with nitrogen is l-lower alkyl-4-piperazinyl, e.g., (IX), affords the urethans (X), which on saponification furnish the l-piperazinyl derivatives (Xl The transformations of (IX) to the l-piperazinyl derivatives (Xl) are illustrated schematically below.

R1 =c is s wherein R, R R R R R,, R,, and n are as defined hereinbefore.

The compounds of this invention are physiologically active having an antidepressant effect upon the central nervous system. The administration antidepressant properties of the novel compounds are shown by measuring the ability of the compounds to counteract depression induced in animals by the administration of tetrabenzaine hexamate, a well-known central nervous system depressant. Generally, the compounds of this invention shown antidepressant activity at dosage levels which produce neither overt stimulation nor depression.

In the test procedure. graded doses of the present compounds to be tested are administered to groups of mice, and this is followed by administering a dose of tetrubenazine hexamate which is known to markedly depress the exploratory behavior of normal mice. Control groups of mice are not given the test compound. The antidepressant treated groups (i.e., groups given the test compound) show normal exploratory behavior, while the control groups, and groups treated with an ineffective antidepressant agent. do not show this normal exploratory behavior, but in contrast show the well-known, profound depression induced by tetrabenazine hexamate.

The results obtained from several dose levels are used to establish effective dose ranges. The active compounds of this invention show their antidepressant properties by this procedure at dose levels which produce little or no untoward reactions, as for example. ataxia or reduced spontaneous motor activity. The present novel compounds, therefore, are useful as effective antidepressant agents, acting upon the central nervous system when administered orally or parenterally, generally in the form of their salts. For oral administration the new compounds of this invention may be incorporated with the usual pharmaceutical excipients and used, for example, in

the form of tablets, capsules dragees, liquids to be administered in drops, emulsions, suspensions and syrups, and in chocolate. candy, and the like. The compounds may also be administered in suppositories, and in sterile suspensions for parenteral injection.

The following examples describe in greater detail the preparation of representative l-vinyl substituted phthalans of the present invention.

EXAMPLE 1 Preparation of 1 ,l-Dimethyl-3-styryl-1l-l-isobenzofurylium Perchlorate To 1,200 ml. of 1.5 molar methyl magnesium bromide in ether stirred at 0 C. is added dropwise an ethereal solution of 100 g. (0.45 mole) of diethylphthalate. The mixture is stirred at 0-5 C. for 2 hours and the resultant complex is decomposed with hydrochloride acid. The organic phase is separated, washed with water and evaporated under reduced pressure leaving an amber oil. The amber oil is dissolved in glacial acetic acid and treated with perchloric acid afiording l ,1 ,3-trimethyl- 1 l-l-isobenzofurylium perchlorate, melting point 162 -164 (3., Dec.

To a warm solution of 2.12 g. (0.0081 mole) of 1,1,3- trimethyl-ll-l-isobenzofurylium perchlorate in 40 ml. of glacial acetic acid is added 1.08 ml. (0.0097 mole) of benzaldehyde. The mixture is stirred and refluxed for 30 minutes, then cooled and filtered affording 2.60 g. of 1,1-dimethyl-3-styryl-l H-isobenzofurylium perchlorate, melting point 187 -l91 C., Dec.

EXAMPLE 2 Preparation of N,N,3 ,3-Tetramethyl- 1 -styryll phthalanpropyl-amine (oxalate) To a stirred, refluxing solution of 3.2 g. (0.02 mole) of 3,3- dimethylphthalide in ml. of tetrahydrofuran is added ml. of a tetrahydrofuran solution of styryl magnesium bromide [from 5.50 g. (0.03 mole) styryl bromide and 720 mg. (0.03 mole) magnesium]. The mixture is stirred while refluxing for 18 hours, then cooled and the complex decomposed with ammonium chloride solution. The organic phase is separated and the aqueous solution extracted with ether. The combined organic solutions are washed with water, dried with magnesium sulfate and evaporated under reduced pressure. The semisolid residue on treatment with petroleum ether (30 60 C.) gives 2.61 g. of 3,3-dimethy1-l-styryl-l-phthalanol, melting point 1 30 l 35 C.

A solution of 1.1 g. of the above 3,3-dimethyl-l-styryl-1- phthalanol in 220 ml. of ether when treated with a solution of perchloric acid in ether produces 1.1 g. of 1,1-dimethyl-3- styryll l-l-isobenzofurylium perchlorate, melting point 183 C.

To a stirred, refluxing solution of dimethylaminopropyl magnesium chloride (from 288 mg. of magnesium and 1.46 g. of dimethylaminopropyl chloride) in 25 ml. of tetrahydrofuran is added portionwise 1.05 g. of 1,1-dimethyl-3-styryl-1l-lisobenzofurylium perchlorate. The mixture is stirred and refluxed for 18 hours, then cooled and decomposed with ammonium chloride solution. The solution is extracted with ether. The ether extract is extracted with percent acetic acid. The acid extract is made alkaline with sodium hydroxide and extracted with ether. This organic extract is washed with water, dried with magnesium sulfate and evaporated under reduced pressure giving 950 mg. of N,N,3,3-tetramethyl-lstyryll -phthalanpropylarnine as a gum. The oxalate salt melts at 196 97 C., and the fumarate salt melts at 156 -l58 C.

EXAMPLE 3 Preparation of N,N,3,3-Tetramethyl-l-(p-methylstyryl)-1- phthalanpropylamine (oxalate) 1n the manner described in example 1 from 920 mg. of 1,1,3'trimethy1-l H-isobenzofurylium perchlorate and 0.41 ml. of 4-methylbenzaldehyde is obtained 1.13 g. of 1,1-dimethyl- 3-(p-methylstyryl)-lH-isobenzofurylium perchlorate, melting point 210 -212 dec.

1n the manner described in example 2using 1.13 g. of 1,1- dimethyl-3-(p-methylstyryl)-1H-isobenzofurylium perchlorate in place of 1,1-dimethy1-3-styryl-ll-l-isobenzofurylium perchlorate there is obtained the oxalate salt of N,N,3,3-tetramethyl- 1 p-methylstyryl lphthalanpropylamine, melting point 186 -l 88 C.

EXAMPLE 4 Preparation of N,N,3,3-tetramethyl-1-(p-methoxystyryl)-1- phthalanpropylamine (oxalate) In the manner described in example lfrom 800 mg. of 1,1,3- trimethyl-ll'l-isobenzofurylium perchlorate and 0.37 ml. of 4- methoxybenzaldehyde is obtained 1.11 g. of 1.1-dimethyl-3- (p-methoxystyryl)- l l-l-isobenzofurylium perchlorate, melting point 225 -228 C., dec.

Following the procedure described in example 2 using 1.1 1 g. of 1,1-dimethyl-3-(p-methoxystyryl)-lH-isobenzofurylium perchlorate there is obtained the oxalate salt of N,N,3,3- tetramethyl- 1 -(p-methoxystyryl 1 -phtha1anpropylamine, melting point 198 -200 C. The hydrochloride salt melts at 164 -165 C.

EXAMPLE 5 Preparation of N,N,3,3-Tetramethyl- 1 -(p'chlorostyryl)- l phthalan-propylamine (oxalate) Following the procedure described in example 1 from 950 mg. of 1,1,3-triemthyl-ll-l-isobenzofurylium perchlorate and 616 mg. of 4-chlorobenzaldehyde is obtained 1.28 g. of 1.1- dimethyl-3-(p-chlorostyryl )-l l-l-isobenzofurylium perchlorate, melting point 195 l98 C., dec.

In the manner described in example 2 using 1.28 g. of 1,1- dimethyl-3p-chlorostyryl lH-isobenzofurylium perchlorate there is obtained the oxalate salt of N,N,3,3-tetramethyl- 1 pchlorostyryl)- 1 -phthalanpropylamine, melting point 222 "-223" C.

EXAMPLE 6 Preparation of N,N,3,3Tetramethyll -(m-chlorostyryl l phthalanpropylamine.

EXAMPLE 7 Preparation of N,N,3,3-Tetramethyl-l-(m-methylstyryl)- l phthalan-propylamine 1n the manner described in example 1 from 1.3 g. of 1,1,3- trimethyl-lH-isobenzofurylium perchlorate and 0.71 ml. of 3- methylbenzaldehyde is obtained 1.41 g. of 1,1-dimethyl-3-(mmethylstyryl )-1H-isobenzofurylium perchlorate, melting point 1 C., dec.

In the manner described in example 2 using 1.41 g. of 1,1- dimethyl-3-( m-methylstyryl l H-isobenzofurylium perchlorate in place of 1,l-dimethyl-3-styryl-ll-l-isobenzofurylium perchlorate there is obtained the oxalate salt of N,N,3 ,3-tetramethyll m-methylstyryl 1 -phthalanpropylamine, melting point 206 207 C.

EXAMPLE 8 Preparation of N,N,3,3-Tetramethyll 3,4-dimethoxystyryl l-phthalanpropylamine Following the procedure described in example 1 from 2.15 g. of 1,1,3-trimethyl-ll-l-isobenzofurylium perchlorate and 1.63 g. of 3,4-dimethoxybenzaldehyde, there is obtained 3.08 g. of 1,l-dimethyl-3-(3,4-dimethoxystyryl)-1H-isobenzofurylium perchlorate, melting point 235 C., dec.

When the procedure of example 2 is followed using 1,1- dimethyl-3-( 3 ,4-dimethoxystyryl l l-l-isobenzofurylium perchlorate in place of l,l-dimethyl-3-styryl-ll-l-isobenzofurylium perchlorate there is obtained N,N,3,3-tetramethyl-l- (3,4-dimethoxystyry1)-l-phtha1anpropylamine as a colorless oil. This product is purified by liquid partition chromatography on a diatomaceous silica support. The nmr spectrum of this substance has resonances at 92,95(C(CH 129 (N(CH,),229,231(OCH,), 380 and 388 c.p.s. (vinyl H).

EXAMPLE 9 3 Preparation of N-Carbethoxy-N,3 ,3-trimethyl l -sytryl- 1- phthalan-propylamine To a solution of 420 mg. of N,N,3,3-tetramethyl-l-styry1-lphthalanpropylamine (prepared as in example 2) in 10 ml. of benzene is added dropwise 0.50 ml. of ethyl chlorocarbonate.

' Themixture is stirred at 25 C. for minutes and then at 40 C. for 2 hours. The solution is cooled and washed with 2 N hydrochloric acid and water, then dried with magnesium sulfate and evaporated under reduced pressure giving 395 mg. of N-carbethoxy-N, 3,3-trimethyll -styry1- l -phthalanpropylamine as a gum.

EXAMPLE 10 Preparation of N,3,3-Trimethyl-1-styry1-l- I phthalanpropylamine furnarate A mixture of 395 mg. of N-carbethoxy-N, 3,3-trimethyl-lstyryl-1-phthalanpropylamine, prepared as described in example 9 in 5 ml. of diethyleneglycol monomethyl ether and 400 mg. of potassium hydroxide in 0.4 ml. of water is stirred and refluxed for 18 hours. The mixture is cooled and poured into 30 ml. of water. The aqueous solution is extracted with ether and the extracts washed with water. The ether solution is extracted with 20 percent acetic acid. The acid solution is made alkaline with sodium hydroxide and extracted with ether. The ether extract is washed with water, dried with magnesium sulfate and evaporated under reduced pressure producing N,3,3-trimethyl-l-styryl-l-phthalanpropylamine as a gum. The fumarate salt melts at 153 -l55 C.

EXAMPLE 1 1 Preparation of N,N,-Dirnethy1-1-styryll phthalanpropylamine When the procedure of example 2 is followed using phthalide in place of 3,3-dimethylphthalide there is formed l-styryll-phthanol.

1n the manner described inexample 2 treatment of the above l-styryl-l-phthanol with dimethylaminopropyl magnesium chloride gives 4-dimethylamino-l-styry1-1-( 2-hydroxymethylpheny1)-butanol.

A solution of 500 mg. of the above 4-dimethy1amino-lstyryl-l-(2-hydroxymethylphenyl)butanol in 2 ml. of 37 percent hydrochloric acid solution is heated at 90l00 C. for 15 minutes. The solution is poured onto cracked ice, and the mixture is extracted with ether. The ether extracts are discarded, and the aqueous solution is rendered alkaline with potassium hydroxide. The mixture is extracted with ether and evaporation of the dried ethereal solution gives N,N,-dimethyl-lstyryl- 1 -phthalanpropy1amine.

EXAMPLE 12 Preparation of N,N ,3,3-Tetramethyl- 1 -(p-methoxystyry1- l phthalanisobutylamine By the procedure of example 2, treatment of N,N,3,3-tetramethyl-1-(p-methoxystyryl)-l-phthalanisobutylamine, the oxalate salt of which has melting point 187 -l 90 O EXAMPLE 13 Preparation of N,N,-Diethyl-3,3-dimethyl-l-(pmethoxystyryl)-1-phthalanpropylamine Treatment of diethylaminopropyl magnesium chloride (from 960 mg. of magnesium and 6.00 g. of diethylaminopropyl chloride) in ml. of tetrahydrofuran with 3.78 g. of l,1-dimethyl-3-(p-methoxystyryl)-1H- isobenzofurylium perchlorate by the procedure described in example 2 produces N,N,-diethyl-3,3-dimethyl-l-(p-methoxystyryl)-l-phthalanpropylamine, boiling point 188 C., at 0.12

mm. of mercury pressure.

dimethylaminoisobutyl magnesium chloride (from 960 mg. of

EXAMPLE 14 Preparation of N,N,3,3-Tetramethyll -(p-cyc1ohexylstyryl)- l phthalanpropylamine In the manner described in example 1, 1,1-dimethyl-3-(pcyclohexylstyryl l l i-isobenzofurylium perchlorate is prepared from 1, l ,3-trimethyl-Iii-isobenzofurylium perchlorate and p-cyclohexylbenzaldehyde.

When the procedure of example 2 is followed using l,ldimethyl-3-(p-cyclohexylstyryl)-Ill-isobenzofurylium perchlorate in place of l,l-dimethyl-3-styryl-lH-isobenzofurylium perchlorate there is obtained N,N,3,3-tetramethyl-l- (p-cyclohexy1styryl)- l -phtha1anpropylamine.

EXAMPLE 15 Preparation of N ,N,3,3-Tetramethyl-l-[2-( 2-thienyl)vinyl]- l phthalanpropylamine Using the procedure of example 1, treatment of 1.10 g. of 1,l,3-trimethyl-lH-isobenzofurylium perchlorate with 0.61 g. of thiophene-2-carboxaldehyde in 20 ml. of glacial acetic acid afi'ords 1.43 g. of l,l-dimethyl-3[2-(2-thienyl)vinyl]-l-H- isobenzofurylium perchlorate as crystals, melting point 196- 198 C., dec.

Treatment of dimethylaminopropyl magnesium chloride (from 392 mg. of magnesium tumings and 1.96 g. of dimethylaminopropylchloride) in tetrahydrofuran with 1.43 g. of l, l -dimethyl-3-[ 2-( 2-thienyl)vinyl]- l H-isobenzofurylium perchlorate as described in example 2afiords N,N,3,3- tetramethyl-l-[2-(2-thienyl)vinyl]-l-phthalanpropylamine, the oxalate salt of which crystallizes from ethanol as white crystals, melting point 18 l l 83 C.

EXAMPLE 16 Preparation of 4-[3-(3,3-Dimethy1- l-p-methoxystyryl-l phthalan)-propyl]morpholine By the procedure of example 2 reaction of l,l-trimethyl-3- (p-methoxystyry1)-Ill-isobenzofurylium perchlorate with 3- (4-morpholinyl)propyl magnesium chloride gives 4-[3-(3,3- dimethyl-1-p-methoxystyryl-l-phthalan)propyllmorpholine.

EXAMPLE 17 Preparation of N,N,3,3-Tetramethyl- 1 -(3,4,5- trimethoxystyryl)- 1 -phthalanpropylamine Oxalate In the manner described in example 1, reaction of 1.09 g. of l,l,3-trimethyl-Ill-isobenzofurylium perchlorate with 0.89 g. of 3,4,5-trimethoxybenza1dehyde in 20 ml. of glacial acetic acid gives 600 mg. of 1,l-dimethyl-3-(3,4,5-trimethoxystyryl)- ll-l-isobenzofurylium perchlorate, melting point 1 82- 1 84 C.

By the procedure of example 2, treatment of dimethylaminopropyl magnesium chloride (from 134 mg. of magnesium and 675 mg. of dimethylaminopropylchloride) in tetrahydrofuran with 600 mg. of l,l-dimethyl-3-(3,4,5-

trimethoxystyryl)-lH-isobenzofurylium perchlorate furnishes N,N,3 ,3-tetramethyl1 l-( 3,4,5-trimethylstyryl)- l -phthalanpropylamine, the oxalate salt of which crystallizes as a hydrate from ethanol in the form of white crystals, melting point l321 35 C.

EXAMPLE l8 Preparation of l-[3-( 3,3-Dimethyl-l -p-methoxystyryll phthalan )-propyl ]pyrrolidine By the procedure of example 2 reaction of l,l-trimethyl-3- (p-methoxystyryl)-lH-isobenzofurylium perchlorate with 3- (l-pyrrolidino)propyl magnesium chloride affords l-[3-(3,3- dimethyll -p-methoxystyryll -phthalan )propyl]pyrrolidine.

EXAMPLE 19 Preparation of N,N,3,3-Tetramethyll -(p-phenylstyryl)- l phthalanpropylamine Oxalate EXAMPLE 20 Preparation of N-Butyl-N,3,3-trimethyl-l-(p-methoxystyryl)- l-phthalanpropylamine By the procedure of example 2, reaction of l,l-trimethyl-3- (p-methoxystyryl)-lH-isobenzofurylium perchlorate with 3- (N-butyl-methylamino)propyl magnesium chloride produces N-butyl-N,3,3-trimethyl-l-(p-methoxystyryl)-l-phthalanpropylamine.

EXAMPLE 2l Preparation of l-(3,3-Dimethyl-l-styryl-lphthalanpropyl)piperidine Treatment of 3-(1-piperidino)propyl magnesium chloride (from 830 mg. of magnesium and 5.58 g. of 1-(3- chloropropyl)-piperidine) in 20 ml. of tetrahydrofuran with 3 .00 g. of l, l -dimethyl-3-styryll H-isobenzofurylium perchlorate in the manner described in example 2 affords l- (3,3-dimethyll -styryll -phthalanpropyl)piperidine, the oxalate salt of which crystallizes from water or ethanol as white crystals, melting point l45l47 C.

EXAMPLE 22 Preparation of N,N,3,3-Tetramethyll -(p-methoxystyryl)- 1 phthalanbutylamine By the procedure of example 2 reaction of l,l-trimethyl-3- (p-methoxystyryl)-lH-isobenzofurylium perchlorate with 4- dimethylaminobutyl magnesium chloride affords N,N,3,3- tetramethyll p-methoxystyryl)- l -phthalanbutylamine.

EXAMPLE 23 Preparation of N,N,3,3-Tetramethyll -(a-methylstyryl)- l phthalanpropylamine To a stirred, refluxing solution of 3.2 g. (0.02 mole) of 3,3- dimethylphthalide in ml. of tetrahydrofuran is added ml. of a tetrahydrofuran solution of a-methylstyryl magnesium bromide [from 5.91 g. (0.03 mole) of B-bromo-a-methylstyrene and 720 mg. (0.03 g.-atom) of magnesium]. The mixture is stirred at reflux temperature for l8 hours, cooled to ice-bath temperature and treated with ammonium chloride solution. The mixture is extracted with ether, and the dried extracts are evaporated under reduced pressure to furnish 3,3- dimethyl-l-(a-methy]styryl)-l phthalanol.

A solution of the above 3,3- dimethyl-l-(a-methylstyryl )-l phthalanol in ether is treated with a solution of perchloric acid in ether to afford l,l-dimethyl-3-(a-methylstyryl)-lH- isobenzofurylium perchlorate.

To a stirred solution of dimethylaminopropyl magnesium chloride (from 288 mg. of magnesium and 1.46 g. of dimethylaminopropyl chloride) in 25 ml. of tetrahydrofuran is added in several portions l.l3 g. of the above l,l-dimethyl-3- (a-methylstyryl)-ll-l-isobenzofurylium perchlorate. The mixture is heated at reflux for 6 hours, then cooled, decomposed with saturated ammonium chloride, and extracted with ether. The ether solution is extracted with 20 percent acetic acid, and the acid extracts are rendered alkaline by addition of potassium hydroxide pellets. The resulting mixture is extracted with ether, and the dried extracts are evaporated to give N,N,3,3-tetramethyl-3-(a-methylstyryl l -phthalanpropylamine.

EXAMPLE 24 Preparation of l-Methyl-4-[(3,3-dimethyll -styryl l phthalanpropyl ]piperazine By the procedure of example 2, treatment of 4-methyl-lpiperazinylpropyl magnesium chloride (from 960 mg. of magnesium and 7.08 g. of 4-methyl-l-piperazinylpropyl chloride) in tetrahydrofuran with 3.48 g. of l,l-dimethyl-3-styryl-ll-lisobenzofurylium perchlorate gives l-methyl-4-[(3,3- dimethyll -styryl)- l -phthalanpropyl ]piperazine.

EXAMPLE 25 Preparation of l-Carbethoxy-4-[ 3,3-dimethyll -styryl l phthalanpropyl l-piperazine A solution of l-methyl-4-[(3,3-dimethyll-styryl)-lphthalanpropyl]piperazine in benzene is treated with ethyl chlorocarbonate. The mixture is stirred at ambient temperatures for 2 hours whereafter it is washed successively with 2 N hydrochloric acid solution and water. The dried organic solution is evaporated under reduced pressure to furnish l-carbethoxy-4-[(3,3-dimethyl-l-styryl)-l-phthalanpropy|]piperazine.

EXAMPLE 26 Preparation of l-[(3,3dimethyll -styryl)-l-phthalanpropyl1- piperazine A mixture of 4l0 mg. of l-carbethoxy-4-[(3,3-dimethyl-lstyryl l -phthalanpropyl ]piperazine in 5 ml. of diethyleneglycol monomethyl ether and 450 mg. of potassium hydroxide in 0.5 ml. of water is stirred at reflux temperature for 18 hours. The mixture is cooled and poured into water. The aqueous solution is extracted with ether, and the extracts are washed with water. The organic solution is extracted with 20 percent acetic acid, and the combined acid extracts are rendered alkaline with potassium hydroxide. The resulting mixture is extracted with ether, and the dried ethereal extracts are evaporated under reduced pressure to furnish l-[(3,3- dimethyll -styryl l -phthalanpropyl ]piperazine.

EXAMPLE 27 Preparation of N,N,3,3-Tetramethyl-l-(p-bromostyryl)- l phthalanpropylamine In the manner described in example 1 from 2.00 g. of l, l ,3- trimethyll H-isobenzofurylium perchlorate and pbromobenzaldehyde is obtained, 2.88 g. of l,l-dimethyl-3-(pbromostyryl)-lH-isobenzofurylium perchlorate, melting point l96-l 99 C. dec.

In the manner described in example 2. using l,l-dimethyl-3- (p-bromostyryl)-lH-isobenzofurylium perchlorate in place of l l-dimethyl-3-styryll H-isobenzofurylium perchlorate, there is obtained N,N,3,3-tetramethyl-1-(p-bromostyryl)-lphthalanpropylamine, the oxalate salt of which has melting point 2 l 9220 C.

EXAMPLE 28 Preparation of N,N,3,3-Tetramethyl- 1 -(p-methoxystyryl)- l phthalanpentylamine By the procedure of example 2, reaction of l,l-trimethyl-3- (p-methoxystyryl)-lH-isobenzofurylium perchlorate with 5- dimethylaminopentyl mangesium chloride produces N,N,3,3- tetramethyll p-methoxystyryll -phthalanpentylamine.

EXAMPLE 29 Preparation of N,N,3,3-Tetramethyl-l-[2-( 2-naphthyl)vinyl]- l-phthalanpropylamine In the manner described in example l from 2.0 g. of l,l,3-

trimethyl-lH-isobenzofurylium perchlorate and 2-naphthaldehyde is obtained 3.00 g. of l,l-dimethy]-3-[2-( 2-naphthyl)- vinyl]-lH-isobenzofurylium perchlorate, melting point 243 C., dec.

In the manner described in example 2 using 1,1-dimethyl-3- [2-( Z-naphthyl )vinylll H-isobenzofurylium perchlorate in place of l, l -dimethyl-3-styryll H-isobenzofurylium perchlorate there is obtained N,N,3,3-tetramethyl-l[2-(2- naphthyl)vinyl]-l-phthalanpropylamine, the oxalate salt of which melts at l55-l65 C.

EXAMPLE 30 Preparation of N,N,3,3-Tetramethyll 2-(5-indanyl)vinyl l-phthalanpropylamine ln the manner described in example I from 2.1 g. of 1,1,3- trimethyl-lH-isobenzofurylium perchlorate and S-indanecarboxaldehyde is obtained 3.05 g. of l,l-dimethyl-3-[2-(5-indanyl)vinyl]-lH-isobenzofurylium perchlorate, melting point 204205 C.

In the manner described in example 2 using l,l-dimethyl-3- [2-(5-indanyl)vinyl]-lH-isobenzofurylium perchlorate in place of l, l -dimethyl-3-styryll H-isobenzofurylium perchlorate, there is obtained N,N,3,3-tetramethyl-l-[2-(5-indanyl )vinyll-l-phthalanpropylamine, the oxalate salt of which melts at l96 l 98 C.

EXAMPLE 3] Preparation of N ,N,3,3-Tetramethyl-l-[2-( l-naphthyl)vinyl]- l-phthalanpropylamine Using the procedure described in example I, from 2.1 g. of 1,l,3-trimethyl-lH-isobenzofurylium perchlorate and lnaphthaldehyde there is obtained 2.93 g. of 1,l-dimethyl-3-[ 2-( l-naphthyl)vinyl]- l H-isobenzofurylium perchlorate, melting point 209-2 C.

In the manner described in example 2 using l,l-dimethyl-3- 2-( 1-naphthyl)vinyl]- l H-isobenzofurylium perchlorate in place of I l-dimethyl-3-styryll H-isobenzofurylium perchlorate there is obtained N,N,3,3-tetramethyl-l [2-( lnaphthyl)vinyl]-l-phthalanpropylamine, the oxalate salt of which melts at l9l192 C.

EXAMPLE 32 Preparation of N,N,3,3-Tetramethyll -[2-( 4-methoxyl naphthyl )-vinyl l -phthalanpropylamine When the procedure described in example I is used from 2.l g. of l, l ,3-trimethyl-lH-isobenzofurylium perchlorate and L86 g. of 4-methoxy-l-naphthaldehyde is obtained 3.42 g. of l,l-dimethyl-3-[2-(4-methoxy-l-naphthyl)vinyl]-1H- isobenzofurylium perchlorate, melting point 252 C.. dec.

In the manner described in example 2 using l,l-dimethyl-3- [2-(4-methoxyl -naphthyl)vinyl]- l H-isobenzofurylium perchlorate in place of l,l-dimethyl-3-styryl-lH-isobenzofurylium perchlorate there is obtained N,N,3,3-tetramethyl-l-[ 2-(4-methoxyl -naphthyl)vinyl] l -phthalanpropylamine, the oxalate salt of which melts at l58-l 70 C.

EXAMPLE 33 Preparation of N,N,3,3-Tetramethyl-l-( p-isopropylstyryl)- l phthalanpropylamine EXAMPLE 34 Preparation of N,N3,3-Tetramethyl-l-[2-( 2-furyl )vinylll phthalanpropylamine Using the procedure described in example I, from 2.1 g. of l,l,3-trimethyl-lH-isobenzofurylium perchlorate and 0.96 g. of Z-furancarboxaldehyde there is obtained 2.35 g. of 1,1- dimethyl-3-[ 2-( 2-furyl )vinyl]- l H-isobenzofurylium perchlorate, melting point 169-l 70 C., dec.

ln the manner described in example 2 using l,l-dimethyl-3- [2-(2-furanyl)vinyl]-lH-isobenzofurylium perchlorate in place of l, I -dimethyl-3-styryll H-isobenzofurylium perchlorate there is obtained N,N,3,3-tetramethyl-l-[2-(2-furyl)vinyl]-l-phthalanpropylamine, the oxalate salt of which melts at l65-l67 C.

EXAMPLE 35 Preparation of 3,3-Diethyl-N,N-dimethyll p-methoxy-B- methylstyryl l -phthalanpropylamine To a stirred, boiling solution of 20 ml. of 3 M etheral ethyl magnesium bromide in ml. of tetrahydrofuran is added dropwise over 20 minutes a solution of 9.50 g. of 3,3- diethylphthalide in 50 ml. of tetrahydrofuran. The solution is stirred and heated at reflux temperature for 1 hour after completion of the addition. The solution is cooled in an icebath and treated with 30 ml. of a saturated ammonium chloride solution followed by l0 ml. of a 20 percent hydrochloric acid solution. The organic phase is separated, and the aqueous phase is extracted with ether. The combined organic solutions are washed successively with water, and 5 percent sodium carbonate solution and water, dried with ma'gnesium sulfate and evaporated under reduced pressure to furnish 2-( l-ethyl-l-hydroxpropyl)propiophenone as an amber oil.

A solution of 1.08 g. of the above Z-(ethyl-I-hydroxypropyl)propiophenone and 0.65 ml. of p-methoxybenzaldehyde in l0 m]. of glacial-acetic acid is treated with 0.42 ml.

of 70-72 percent perchloric acid and stirred at ambient temperature for minutes. An additional 0.65 ml. of p-methoxybenzaldehyde is added and the solution is heated at reflux temperature for 30 minutes. The solution is cooled in an icebath and addition of 30 ml. of ether causes the 1.34 g. of l,l-diethyl-3-(p-methoxy-/3-methylstyryl)-lH- isobenzofurylium perchlorate as red crystals, melting point l45-147 C., dec.

When the procedure of example 2 is followed, using l,ldiethyl-3-(p-methoxy-B-methylstyryl l l-l-isobenzofurylium perchlorate in place of l,l-dimethyl-3-styryl-lH-isobenzofurylium perchlorate, there is obtained the oxalate salt of 3,3- diethyl-N ,N-dimethyll p-methoxy-B-methylstyryl l phthalanpropylamine, melting point 94-98 C.

EXAMPLE 36 Preparation of l 3-[ 3,3-Dimethyl-l-(p-methylstyryl)- l phthalanyll-propyl'} trimethylammonium iodide To a solution of 320 mg. of N,N,3,3-tetramethyl-l-(pmethylstyryl)-l-phthalanpropylamine in 30 ml. of ether is added a solution of 1.0 ml. of methyl iodide in ml. of ether. The resultant precipitate is collected after 18 hours and recrystallized from acetone-petroleum ether (60) affording 264 mg. ofwhite crystals, melting point l79-l 80 C.

EXAMPLE 37 Preparation of N,N.3.3-Tetramethyl-l-(mtrifluoromethylstyryl l -phthalanpropylamine We claim: 1. A substituted phthalan of the formula:

precipitation of 5 wherein R and R are members selected from the group con sisting of hydrogen and lower alkyl; R;, is a member selected from the group consisting of hydrogen, lower alkyl, and lower alkoxycarbonyl; R is lower alkyl; R and R taken together with nitrogen Rs N is a member selected from the group consisting of 4-morpholinyl, pyrrolidinyl, piperidinyl, l-lower alkyl-4-piperazinyl, lpiperazinyl and blower alkoxy carbonyl-4-piperazinyl; R, is selected from the group consisting of hydrogen and lower alkyl; R m are members selected from the group consisting of hydrogen, and lower alkyl; R is a member selected from the group consisting of thienyl, furyl, indanyl, naphthyl, lower alkoxynaphthyl, phenyl, cyclohexylphenyl, halophenyl. lower alkylphenyl. methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, and biphenyl; n is an integer of l to 3, and nontoxic acid addition salts thereof.

2. The substituted phthalan according to claim 1: N,N,3.3- tetramethyl l -styryll -phthalanpropylamine.

3. The substituted phthalan according to claim I: N,N,3.3- tetramethyll p-methylstyryl l -phthalanpropylamine.

4. The substituted phthalan according to claim 1: N,N,3,3-

tetrameth l-l- -methox st l)-lhthalan ro ylamine.

5. The ubst t uted ph al h acco ding to t Jair n l: N.N,3,3'

tetramethyll o-methylstyryl l -phthalanpropylamine.

6. The substituted phthalan according to claim 1: N,N.3.3- tetramethyll 3 ,4-dimethoxystyryl l -phthalanpropylamine.

7. The substituted phthalan according to claim 1: N.N,3,3- tetramethyl-l-[2-(2-furyl)vinyll-l-phthalanpropylamine.

8. The substituted phthalan according to claim l: N.3,3- trimethyll -styryll -phthalanpropylamine. 

2. The substituted phthalan according to claim 1: N,N,3,3-tetramethyl-1-styryl-1-phthalanpropylamine.
 3. The substituted phthalan according to claim 1: N,N,3,3-tetramethyl-1-(p-methylstyryl)-1-phthalanpropylamine.
 4. The substituted phthalan according to claim 1: N,N,3,3-tetramethyl-1-(p-methoxystyryl)-1-phthalanpropylamine.
 5. The substituted phthalan according to claim 1: N,N,3,3-tetramethyl-1-(o-methylstyryl)-1-phthalanpropylamine.
 6. The substituted phthalan according to claim 1: N,N,3,3-tetramethyl-1-(3,4-dimethoxystyryl)-1-phthalanpropylamine.
 7. The substituted phthalan according to claim 1: N,N,3,3-tetramethyl-1-(2-(2-furyl)vinyl)-1-phthalanpropylamine.
 8. The substituted phthalan according to claim 1: N,3,3-trimethyl-1-styryl-1-phthalanpropylamine. 